Abstract
Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells1. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis3,4,5. We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17–92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17–92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.
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Acknowledgements
We thank O. Van Goethem, H. Stephan and M. Baumann for excellent technical advice and/or assistance. We thank M. Skipper for helpful comments on the manuscript and G. Hannon (Watson School of Biological Sciences, Cold Spring Harbor Laboratory, USA) for providing the Dicer1 floxed mice. This work was supported in part by FWO, the Belgian Foundation against Cancer (BFK), Geconcerteerde Onderzoek Aangelegenheden (GOA, KULeuven, Belgium) and the German Federal Ministry of Education and Research, BMBF (NGFNplus, ENGINE) as well as the EU (FP7, ONCOMIRS, Contract 201102). This publication reflects only the authors’ views. The commission is not liable for any use that may be made of the information herein.
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D.N. and I.L. performed experimental work, developed the hypothesis, analysed the data and coordinated the project. F.C. and C.K. performed the transfection studies in the human retinoblastoma cells and analysed the data. P.M. performed the miR-profiling experiments and analysed the data. S.J.N. contributed to the design of the miR-inhibition experiments. A.J. generated and characterized the Y79 p53KD cell line. A.S. and J.H.S. provided the human retinoblastoma samples. F.S., J.V., M.A.D., A.S. and J.H.S. discussed the hypothesis and contributed to data interpretation and experimental design. J-C.M. conceived the hypothesis, led the project, interpreted the data and wrote the manuscript.
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Nittner, D., Lambertz, I., Clermont, F. et al. Synthetic lethality between Rb, p53 and Dicer or miR-17–92 in retinal progenitors suppresses retinoblastoma formation. Nat Cell Biol 14, 958–965 (2012). https://doi.org/10.1038/ncb2556
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DOI: https://doi.org/10.1038/ncb2556
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